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Please cite this article in press as: Ayub et al., A Homozygous Nonsense Mutation in the Human Desmocollin-3 (DSC3) Gene UnderliesHereditary Hypotrichosis and Recurrent Skin..., The American Journal of Human Genetics (2009), doi:10.1016/j.ajhg.2009.08.015
REPORT
A Homozygous Nonsense Mutation in theHuman Desmocollin-3 (DSC3) Gene UnderliesHereditary Hypotrichosis and Recurrent Skin Vesicles
Muhammad Ayub,1,2 Sulman Basit,1 Musharraf Jelani,1 Fazal Ur Rehman,1 Muhammad Iqbal,3
Masoom Yasinzai,2 and Wasim Ahmad1,*
Desmosomes are the major players in epidermis and cardiac muscles and contribute to intercellular binding and maintenance of tissue
integrity. Two important constituents of desmosomes are transmembrane cadherins named desmogleins and desmocollins. The critical
role of these desmosomal proteins in epithelial integrity has been illustrated by their disruption in mouse models and human diseases. In
the present study, we have investigated a large family from Afghanistan in which four individuals are affected with hereditary hypotri-
chosis and the appearance of recurrent skin vesicle formation. All four affected individuals showed sparse and fragile hair on scalp, as
well as absent eyebrows and eyelashes. Vesicles filled with thin, watery fluid were observed on the affected individuals’ scalps and on
most of the skin covering their bodies. A scalp-skin biopsy of an affected individual showed mild hair-follicle plugging. Candidate-
gene-based homozygosity linkage mapping assigned the disease locus to 8.30 cM (8.51 Mbp) on chromosome 18q12.1. A maximum
multipoint LOD score of 3.30 (q ¼ 0.00) was obtained at marker D18S877. Sequence analysis of four desmoglein and three desmocollin
genes, contained within the linkage interval, revealed a homozygous nonsense mutation (c.2129T>G [p.Leu710X]) in exon-14 of the
desmocollin-3 (DSC3) gene.
Desmosomes are cell-adhesion junctions that are required
for connecting adjacent cells and maintaining the integrity
of organs, such as the skin, that are particularly exposed to
mechanical stress. These junctions are composed of assem-
blies of membrane-spanning cadherins and cytoplasmic
plaque constituents. The transmembrane components
comprise four types of desmogleins (DSG1, DSG2, DSG3,
DSG4) and three types of desmocollins (DSC1, DSC2,
DSC3) bridging the extracellular space and are embedded
in the cytoplasmic plaques. The plaque components medi-
ate the anchorage of cadherins with intermediate filaments
through a protein complex consisting of desmoplakin,
plakoglobin, and plakophilins.1
The four desmoglein and three desmocollin genes are
localized adjacent to each other on the long arm of
chromosome 18 (18q12.1) in humans.2,3 A very similar
arrangement of these genes has been found on mouse
chromosome 18, with two additional desmoglein genes
(dsg1b, dsg1g). Most of the desmosomal genes have been
associated with inherited disorders that affect the skin
and its appendages. This includes mutations in plakophi-
lin (PKP1 [MIM 601975]), causing ectodermal dysplasia
with sparse hair and skin fragility;4 desmoplakin (DSP
[MIM 125647]) and plakoglobin (PG [MIM 173325]),
underlying Naxos disease (MIM 601214), characterized
by sparse wooly hair and cardiomypathy;5,6 and desmo-
glein4 (DSG4 [MIM 607892]), causing localized auto-
somal-recessive hypotrichosis (LAH [MIM 607903]).2 The
desmogleins DSG1 and DSG3 also serve as autoantigens
in the epidermal blistering diseases pemphigus foliaceus
and pemphigus vulgaris, respectively.7,8 In a study
1Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam Un
chistan, Quetta, Pakistan; 3Department of Dermatology, Bolan Medical Colleg
*Correspondence: [email protected]
DOI 10.1016/j.ajhg.2009.08.015. ª2009 by The American Society of Human
The
involving a large number of patients with bullous disor-
ders, Muller et al.9 have shown that autoantibodies against
desmocollins are restricted to cases of paraneoplastic
pemphigus (PNP).
In this study, we have investigated a large family with
clinical manifestations of autosomal-recessive hereditary
hypotrichosis and a high degree of consanguinity (Fig-
ure 1). The study was approved by the institutional review
board (IRB) of Quaid-i-Azam University, Islamabad,
Pakistan. The family originated from Kandahr city of
Afghanistan and has four affected individuals, including
one male (IV-6), aged 5 years, and three females (IV-3,
IV-4, IV-5), aged from 12 to 18 years. All of the four affected
individuals underwent examination at a local government
hospital in Pakistan. Affected individuals of the family
showed features of hereditary hypotrichosis. At birth, hairs
were present on the scalp. After ritual shaving, which is
usually performed a week after birth, hairs grew back on
the scalp. The hairs were fragile and started falling again
after 2–3 months (Figure 2). In time, only sparse hair was
left on the scalp. In affected individuals, vesicles (less
than 1 cm in diameter) were observed on the scalp and
skin of most of the body (Figure 2). Mucosal vesicles were
not observed in any of the four affected individuals.
From time to time, these vesicles disappeared but then re-
appeared again. All of the four affected individuals of the
family complained of a bursting of the vesicles with
a release of fluid and the development scars on the skin
site that normally took 3–4 months to heal.
The affected individuals were nearly devoid of normal
eyebrows, eyelashes, axillary hair, and body hair. Teeth,
iversity, Islamabad, Pakistan; 2Institute of Biochemistry, University of Balu-
e, Quetta, Baluchistan, Pakistan
Genetics. All rights reserved.
American Journal of Human Genetics 85, 1–6, October 9, 2009 1
Figure 1. Pedigree of a Consanguineous Family from Afghanistan Segregating Autosomal-Recessive HypotrichosisDouble lines are indicative of consanguineous unions. Clear symbols represent unaffected individuals, whereas filled symbols representaffected individuals. The disease interval is flanked by two markers, D18S66 and D18S1139. For genotyped individuals, haplotypes areshown beneath each symbol, revealing that all affected individuals are homozygous for the same haplotype, whereas normal parentsand healthy siblings are heterozygous carriers between markers D18S66 and D18S1139. Genetic distances in centiMorgans (cM) aredepicted according to the Rutgers combined linkage-physical map (build 36.2).
Please cite this article in press as: Ayub et al., A Homozygous Nonsense Mutation in the Human Desmocollin-3 (DSC3) Gene UnderliesHereditary Hypotrichosis and Recurrent Skin..., The American Journal of Human Genetics (2009), doi:10.1016/j.ajhg.2009.08.015
nails, palms, soles, sweating, and hearing were normal
in all affected individuals. Electrocardiography results
showed that affected individuals had no cardiac abnor-
mality. In one affected individual (IV-3), levels of serum
immunoglobulin-A (IgA), IgE, and IgD, quantitated by
ELISA against control subjects, showed no change. Hetero-
zygous carrier individuals had normal hairs and were clin-
ically indistinguishable from genotypically normal indi-
viduals.
A scalp-skin biopsy of an affected individual (IV-3) of the
family showed slight follicular plugging, a mild presence
of perivascular and periadnexal inflammatory cells, and
normal hair follicles (Figure 2). The sebaceous glands
appear morphologically normal and connected to the
hair follicles.
2 The American Journal of Human Genetics 85, 1–6, October 9, 2009
To identify the gene underlying the hypotrichosis and
skin-vesicle phenotype in the family, we followed a clas-
sical linkage-analysis approach. Linkage in the family was
searched for with the use of highly polymorphic microsa-
tellite markers linked to three genes, including DSG4 (MIM
607892) (markers D18S877, D18S847, D18S36, D18S456,
D18S1133), LIPH (MIM 607365) (markers D3S2314,
D3S1618, D3S3609, D3S3583, D3S3592, D3S1530), and
P2RY5 (MIM 609239) (markers D13S1312, D13S168,
D13S164, D13S273, D13S284, D13S1807).10 Conditions
used for PCR amplification of the microsatellite markers
have been described previously.11
Genotyping data and haplotype analysis showed linkage
in the family to the DSG4 gene on chromosome 18q12.1
(Figure 1). The order of the markers, used in genotyping,
Figure 2. Clinical Findings of Affected Individuals with Hereditary Hypotrichosis(A and B) Affected female individuals IV-3 and IV-5 at 18 and 12 years of age, respectively. Both individuals have sparse and fragile hair onscalp.(C) Right arm of an affected individual, IV-5, showing vesicles on the skin.(D) Scalp biopsy of an affected individual, IV-3. Histological examination shows: hf, hair follicle; epi, epidermis; sg, sebaceous glands; swg,sweat glands.
Please cite this article in press as: Ayub et al., A Homozygous Nonsense Mutation in the Human Desmocollin-3 (DSC3) Gene UnderliesHereditary Hypotrichosis and Recurrent Skin..., The American Journal of Human Genetics (2009), doi:10.1016/j.ajhg.2009.08.015
was based on the National Center for Biotechnology Infor-
mation (NCBI) Build 36.2 sequence-based physical map
(International Human Genome Sequence Consortium
2001). Analysis of all the marker genotypes within this
region with PEDCHECK and MERLIN did not elucidate
any genotyping errors. The results of the two-point12 and
multipoint analyses13 are presented in Table 1. An auto-
somal-recessive mode of inheritance with complete pene-
trance and a disease-allele frequency of 0.001 were used
Table 1. Multipoint and Two-Point LOD Score Results between the DS
Marker cMa Mbb Multipoint LOD Score
Two-Point LO
0.00 0.
D18S66 53.51 22.38 �N �N �1
D18S478 54.85 23.40 0.17 1.28 1
D18S877 56.26 24.97 3.30 2.48 2
D18S847 57.41 25.95 3.29 2.48 2
DSC3 N/A 26.85
DSC2 N/A 26.91
DSC1 N/A 26.96
DSG1 N/A 27.16
DSG4 N/A 27.23
DSG3 N/A 27.29
DSG2 N/A 27.35
D18S36 59.09 27.41 3.29 2.68 2
D18S47 59.33 28.03 3.28 2.68 2
D18S456 60.41 29.41 3.26 2.48 2
D18S1124 60.90 29.66 3.08 2.48 2
D18S1133 60.90 30.35 2.27 0.98 0
D18S1139 61.81 30.89 �N �N �3
a Average-sex genetic distance in centiMorgans (cM), according to Rutgers comb The physical position is based according to build 36.2 of the human genome (
The
in the analysis. The highest two-point LOD score at zero
recombination fraction (q ¼ 0.00) of 2.68 was obtained at
markers D18S36 and D18S547. Multipoint analysis gener-
ated a maximum LOD score of 3.30 with marker D18S877.
Haplotypes were constructed with the use of SIMWALK214
for determination of the critical recombination events in
the family. The centromeric boundary of the interval corre-
sponds to a recombination event between markers D18S66
(53.51 cM) and D18S478 (54.85 cM), which occurred in
C3 Gene and Chromosome 18 Markers
D Score at Recombination Fraction q ¼
01 0.05 0.10 0.20 0.30 0.40
.36 �0.17 0.19 0.35 0.28 0.13
.25 1.15 1.01 0.74 0.46 0.18
.42 2.20 1.91 1.34 0.77 0.25
.42 2.20 1.91 1.34 0.77 0.25
.63 2.39 2.09 1.49 0.89 0.34
.63 2.39 2.09 1.49 0.89 0.34
.42 2.20 1.91 1.34 0.77 0.25
.42 2.20 1.91 1.34 0.77 0.25
.96 0.88 0.77 0.56 0.35 0.14
.55 �1.65 �0.97 �0.45 �0.20 �0.05
bined linkage-physical human genome map.25
International Human Genome Sequence Consortium, 2001).
American Journal of Human Genetics 85, 1–6, October 9, 2009 3
Figure 3. Sequence Analysis of the DSC3 Gene Mutationc.2129T > G in the FamilyPartial DNA sequence of the DSC3 gene from (A) a homozygous(affected) individual, showing a transversion (T>G); (B) a heterozy-gous carrier; and (C) a control individual, showing wild-typesequence. Arrows indicate position of the mutation.
Please cite this article in press as: Ayub et al., A Homozygous Nonsense Mutation in the Human Desmocollin-3 (DSC3) Gene UnderliesHereditary Hypotrichosis and Recurrent Skin..., The American Journal of Human Genetics (2009), doi:10.1016/j.ajhg.2009.08.015
affected individual IV-3. A recombination event between
markers D18S1133 (60.90 cM) and D18S1139 (61.81 cM)
in affected individuals IV-3 and IV-5 defined the telomeric
boundary of the disease interval. The linkage interval
flanked by markers D18S66 and D18S1139 contains 8.30
cM, which is 8.51 Mbp long according to Rutgers combined
linkage-physical map (build 36.2) of the human genome.
This region contains 30 genes.
The DSG4 gene (MIM 607892), reported earlier as
involved in hereditary hypotrichosis,2,15 was sequenced
first with the use of primer sequences (Table S1, available
online) in two affected individuals and one normal indi-
vidual in the family. However, the sequence analysis failed
to identify disease-causing variants in the family. Three
other desmoglein genes (DSG1 [MIM 125670], DSG2
[MIM 125671], DSG3 [MIM 169651]), as well as three des-
mocollin genes (DSC1 [MIM 125643], DSC2 [MIM
125645], DSC3 [MIM 600271]), located adjacent to DSG4
on chromosome 18q12.1, were then sequenced. DNA
sequencing was performed with the Big Dye Terminator
v3.1 Cycle Sequencing Kit, together with an ABI Prism
310 Genetic Analyzer (Applera, Foster City, CA, USA).
Sequence variants were identified via the Bioedit sequence
alignment editor, version 6.0.7.
Sequence analysis of the DSC3 gene detected a homozy-
gous nonsense mutation involving a T-to-G transversion at
nucleotide position 2129 (c.2129T>G) in exon 14 of the
gene (Figure 3). To our knowledge, this mutation has not
been previously reported. The mutation resulted in the
conversion of leucine to a premature stop codon at amino
acid position 710 (p.Leu710X).
The pathogenic sequence variant presented here was
found in the heterozygous state in the obligate carriers
and segregated with the disease in the family. To exclude
the possibility that the nonsense mutation does not repre-
sent a nonpathogenic polymorphism, we screened a panel
of 100 unaffected, unrelated, ethnically matched control
individuals, and we did not identify the mutation outside
of the family.
The pivotal role of the desmosomal proteins in epithelial
integrity has been demonstrated by targeted ablation of
the corresponding genes in mice, as well as their by disrup-
tion in human genetic disorders. Mice deficient in Dsc1,
Dsc3, Dsg3, and Dsg4 exhibit skin and hair phenotypes.
Mice carrying a targeted deletion of Dsc31 and Dsg316
develop defective hair anchoring in the telogen phase of
the growth cycle. These mice also exhibit a skin phenotype
that resembles pemphigus vulgaris.1,17 Mice carrying
mutations in Dsc1 and Dsg4 exhibit skin and hair pheno-
types, but defective hair anchoring is not a feature in these
mutants.2,18 In humans, the role of DSG4 in skin has been
established by identification of mutations in families with
inherited hypotrichosis (MIM 607903).2
In the study presented here, we have reported a muta-
tion, which to our knowledge has not been previously
published, in the DSC3 gene in a family originating from
a famous city of Kandahr in Afghanistan. Clinical features
4 The American Journal of Human Genetics 85, 1–6, October 9, 2009
including hypotrichosis and skin vesicles were observed in
all of the affected individuals of the family. These vesicles
burst from time to time, releasing thin, watery fluid.
Such a condition was not reported in any of the patients
carrying mutations in other cadherin genes. The vesicles
observed in our patients were not similar to skin blisters
reported earlier in Dsc3 and Dsg3 null mice.
The 52 kb DSC3 gene contains 16 exons and, along with
two other desmocollins (DSC1 and DSC2), is expressed in
the epidermis. In mouse and human Dsc1/DSC1, expres-
sion is restricted to the uppermost portion of the epi-
dermis,19 Dsc2/DSC2 is very weakly expressed in the basal
layer of the epidermis20 and Dsc3/DSC3 expresses mainly
in the basal and first suprabasal layers of the epidermis.21
DSC3, like other cadherins, is a transmembrane compo-
nent of the desmosomes and comprises of a number of
domains, including a signal sequence (amino acids 1–27),
a propeptide (28–135 amino acids), an extracellular
domain (136–690 amino acids), a transmembrane domain
(691–711 amino acids), and a c-terminal cytoplasmic
domain (712–896 amino acids). The extracellular domain
has been further divided into five cadherin domains
(136–243, 244–355, 356–471, 472–579, and 580–690
amino acids). The first four of these subdomains contain
repeats of approximately of 110 amino acids, and the fifth
subdomain contains four cystein residues. Each cadherin
repeat is an independently folding sequence that contains
motifs with conserved sequences DRE, DXNDNAPXF, and
DXD.22 The multiple cadherin domains form calcium-
dependent rod-like structures with a calcium-binding site
Please cite this article in press as: Ayub et al., A Homozygous Nonsense Mutation in the Human Desmocollin-3 (DSC3) Gene UnderliesHereditary Hypotrichosis and Recurrent Skin..., The American Journal of Human Genetics (2009), doi:10.1016/j.ajhg.2009.08.015
at the domain-domain interface. Calcium ions bind to
specific residues in each cadherin repeat to ensure its
proper folding and confer rigidity upon the extracellular
domain, which is essential for cadherin adhesive function.
The intracellular regions of cadherin repeats interact with
intermediate filaments of the cytoskeleton elements via
desmosomal plaque proteins plakophilin, plakoglobin,
and desmoplakin.23 In addition to mediating cell-cell con-
tact, cadherins are involved in cell fate, signaling, prolifer-
ation, differentiation, and migration.
The nonsense mutation (p.Leu710X) identified in the
family here is located at the junction of the transmem-
brane and the c-terminal cytoplasmic domain of DSC3.
The mutation results in a premature termination codon,
thereby predicted as causing nonsense-mediated decay of
the mRNA or instability of the truncated protein.24 The
role of DSC3 in normal function of desmosomes, mainte-
nance of structural integrity of the interfollicular epi-
dermis, and anchorage of the telogen hair shaft has been
demonstrated in mice.1 These authors have shown that
the skin phenotype of the Dsc3 null mouse is more severe
than that of any other demosomal cadherin null mouse.
The skin blisters reported in Dsc3 null mice1 were not
present in patients in our family. However, skin vesicles
filled with thin, watery fluid were observed in all of the
affected individuals of the family. The hair phenotype in
our patients has some features similar to those of Dsc3
null and Dsg3 null mice.1,16 In all four affected individuals
of the family presented here, hairs were present at birth.
After ritual shaving, hairs reappeared, but patches of hair
loss continued to occur from time to time. This pattern
of hair loss, as described by Chen et al.,1 suggested a defect
in the anchorage of telogen follicles. These authors have
further shown that hair is anchored in the skin by two
epithelial cell layers that surround the lower region of
the hair shaft. Given that both of these cell layers show
high levels of DSC3, it is probable that the absence of
this protein results in loss of cell adhesion and hair loss.
The study reported here demonstrated, to our knowledge
for the first time, a mutation in the human DSC3 gene
that resulted in hair loss and the development of skin
vesicles.
Supplemental Data
Supplemental Data include one table and can be found with this
article online at http://www.cell.com/AJHG/.
Acknowledgments
We are grateful to the patients and their family members for their
participation in the present research work. This work was funded
by the Higher Education Commission (HEC), Islamabad, Pakistan.
Received: June 14, 2009
Revised: July 28, 2009
Accepted: August 28, 2009
Published online: September 17, 2009
The
Web Resources
The URLs for data presented herein are as follows:
International Human Genome Sequence Consortium, 2001,
http://compgen.rutgers.edu/RutgersMap
Online Mendalian Inheritance in Man (OMIM), http://www.ncbi.
nlm.nih.gov/omim/
USCS Genome Bioinformatics, March 2006, http://genome.ucsc.
edu/cgi-bin/hgGateway
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